Abdelghaffar Salous Pre-Doc Fellowship: Role of Lipid Phosphatases in Dynamic Regulation of Lipid Metabolism and Signaling in Cardiovasculature

  • Morris, Andrew (PI)
  • Salous, Abdelghaffar (CoI)

Grants and Contracts Details


The bioactive lipid mediators lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) regulate a broad range of cellular processes. LPA and S1P are present at micromolar concentrations in the blood where genetic and pharmacological evidence implicates them as mediators of vascular inflammation and injury responses, blood pressure and immune function. LPA and S1P are produced by sphingosine kinases and the lysophospholipase D autotaxin respectively. In mouse models, marked declines in circulating levels of LPA and S1P elicited by down regulation of these enzymes and the rapid clearance of intravenously administered LPA and S1P from the circulation suggests that maintenance of steady state circulating levels of these mediators reflects a balance between synthesis and degradation. The long term aim of this research is to identify the enzyme(s) responsible for removal of LPA and S1P from the circulation and to understand their role in regulation of LPA and S1P signaling. Preliminary data suggest that dephosphorylation is the primary mechanism for clearance of LPA and S1P from the circulation. Comparisons between the rate of degradation of LPA and S1P in the blood in live mice or in whole blood ex vivo identify roles for both blood cells and vascular cells, most likely vascular endothelium, in this process. Lipid phosphate phosphatases (LPPs) are a family of integral membrane cell surface enzymes that dephosphorylate LPA, S1P and related molecules. Our central hypothesis is that one or more LPPs is responsible for inactivation of LPA and S1P in the blood. Aim1: To examine the activity and expression of the LPP enzymes in blood and vascular cells. Aim2: To characterize LPA and S1P metabolism in the circulation of mice we have very recently made with inducible tissue specific inactivation of the major vascular endothelial LPP isoform, LPP3. Aim 3: To use cells deficient in LPP3 derived from these animals in conjunction with studies of LPP3 variants engineered to be inactivated by extracellular proteolysis to definitively prove that the ability of overexpressed LPP3 to attenuate signaling responses to LPA is mediated by its cell surface lipid phosphatase activity. This work will provide important new information about an understudied and presently poorly understood aspect of bioactive lipid signaling with obvious implications for the development of small molecule therapeutics targeting these important cardiovascular signaling molecules.
Effective start/end date7/1/096/30/11


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